1. Field of the Invention
The present invention relates to the therapeutic use of retinoids to increase plasma HDL levels for the treatment and prevention of coronary artery disease.
2. Description of the Related Art
High Density Lipoproteins (HDL), a heterogeneous population of spherical particles containing variable amounts of lipids and apolipoprotein, are the most abundant lipoproteins in the plasma. It has recently been observed that low plasma HDL levels are associated with an increased incidence of coronary artery disease (CAD). Numerous epidemiological studies over the last thirty years have verified this association and provided evidence for a putative protective effect of increased HDL levels against CAD; Miller, N. E., Am. Heart J. 113:589-597 (1987). It is believed that HDL plays a fundamental role in the lipid transport system and that HDL represents a site for transient storage of potentially harmful lipids and apolipoproteins which, if they were not packaged into lipoprotein particles, might damage cell membranes because of their potential detergent properties; Eisenberg, S., J. Lipid Res. 25:1017-1058 (1984).
It is known that high-density lipoproteins are involved in a large number of diverse intravascular metabolic processes including the process of reverse cholesterol transport, in which cholesterol from extrahepatic tissue is transported to the liver for conversion to bile acids and eventual excretion. As a result of these observations, research efforts have focused on methods of affecting plasma HDL levels in order to provide protection against CAD.
As stated above, HDL's are spherical particles containing variable amounts of lipoproteins and apolipoproteins. Apolipoprotein AI (Apo AI) is a major protein constituent of plasma HDL and intestinally derived lipoproteins known as chylomicrons. Although recent studies suggest that dietary, hormonal and other environmental factors regulate apo Al gene expression, the molecular basis for the mechanisms involved remain poorly understood. It is known that the gene coding for apolipoprotein Al is expressed predominantly in the liver and intestine. Previous work has shown that hepatocyte-specific expression is determined by synergistic interactions between transcription factors bound to three separate sites with a powerful liver-specific enhancer located in the region -222 to -110 nucleotides upstream of the apolipoprotein Al start site; Widom et al., Mol. Cell Biol., 11:677-687 (1991). In a recent study, it was found that one of the sites in this enhancer is a highly specific retinoic acid-responsive element (RARE) that responds to recently identified retinoic acid receptors (RXR.alpha.); Rottman et al., Mol. Cell Biol., 11:3814-3820 (Jul. 1991). These results suggest that retinoic aid response pathways mediated by RXR.alpha. play a role in apolipoprotein Al expression and ultimately cholesterol and retinoid transport and metabolism.
It has been known for many years that retinoids, the family of molecules comprising both the natural and synthetic analogues of retinol (Vitamin A), are potent agents for control of both cellular differentiation and cellular proliferation; Wolbach et. al., J. Exp. Med., 42:753-777. Retinoids have been reported to modulate the growth and progression of tumors and premalignant lesions, to affect the immune system, to play a role in inflammatory processes, to regulate differentiation of tissues (especially epithelial) and organs and to influence cellular adhesiveness and cellular interactions. See Pawson et al., J. Med. Chem., 25:1269-1277 (1982).
Ringer et al., Am. J. Chem Nutr., 53:688-694 (1991) observed an increase in HDL concentrations in patients given .beta.-carotene, but did not find any changes in apolipoprotein A or B levels. Gollnick et al., Saurat (ed.), Retinoids: New Finds in Research and Therapy, Retinoid Symp., Geneva 1984, pp. 445-460 (Karger, Basel 1985), reported no significant alteration in the HDL and LDL fractions of cholesterol in patients given etretinoate, and a decrease in HDL-cholesterol under isotretinoin. Lyons et al., Br. J. Dermatology, 107:591-595 (1982) observed a decrease in HDL-cholesterol levels in patients given 13-cis-retinoic acid.